The active flares of colitis (collectively referred to as inflammatory bowel disease [IBD]), are characterized by migration of neutrophils to the intestinal lumen forming an intestinal crypt abcess. Such neutrophil movement is directed via polarized chemokine secretion by the epithelial cells that line the intestine. As I transitioned from trainee to faculty, I elucidated the mechanism by which such epithelial chemokine secretion is regulated. Breifly, I found that epithelial Ca++ mobilization is a key signal regulating such chemokine secretion. Further, such chemokine secretion is activated via the protein flagellin that is secreted by bacteria. Flagellin is secreted by commensal and pathogenic bacteria. However, only flagellin that crosses epithelia to the basolateral membrane domain activates epithelial chemokine secretion. Such translocation of flagellin is mediated by pathogens, but not commensal bacteria, explaining why, normally, only pathogenic bacteria induce epithelia to orchestrate inflammation. However, abberent translocation of, and/or responses to, flagellin may occur in IBD and thus may underlie the inappropriate chemokine secretion that occurrs in IBD. For my first independent award application, I propose to expand on the above studies while investigating the hypothesis that bacterial-epithelial interactions regulate the neutrophil infiltration i(i.e, active inflammation) associated with both innate immunity and IBD. Consequently, pharmacologic manipulation of these interactions can be therapeutic for IBD. This hypothesis will be studied in vitro and in vivo via three specific aims, all of which are supported by substantial preliminary data. Specifically, I will characterize bacterial translocation of flagellin across intestinal epithelia, investigate how flagellin activates epithelial chemokine secretion and further define the activation of anti-inflammatory signaling pathways by lipoxins. In vitro and in vivo models will be utilized.